Mepolizumab improvements in health-related quality of life and disease symptoms in a patient population with very severe chronic rhinosinusitis with nasal polyps: psychometric and efficacy analyses from the SYNAPSE study

Background Although the psychometric properties of patient-reported outcome measures (e.g. the 22-item Sino-nasal Outcomes Test [SNOT-22]) in chronic rhinosinusitis with nasal polyps (CRSwNP) have been defined, these definitions have not been extensively studied in patients with very severe CRSwNP, as defined by recurrent disease despite ≥ 1 previous surgery and a current need for further surgery. Therefore, the psychometric properties of the symptoms visual analogue scales (VAS) were evaluated, and meaningful within-patient change thresholds were calculated for VAS and SNOT-22. Methods SYNAPSE (NCT03085797), a randomized, double-blind, placebo-controlled, 52-week trial, assessed the efficacy and safety of 4-weekly mepolizumab 100 mg subcutaneously added to standard of care in very severe CRSwNP. Enrolled patients (n = 407) completed symptom VAS (six items) daily and SNOT-22 every 4 weeks from baseline until Week 52. Blinded psychometric assessment of individual and composite VAS was performed post hoc, including anchor-based thresholds for meaningful within-patient changes for VAS and SNOT-22, supported by cumulative distribution function and probability density function plots. The effect of mepolizumab versus placebo for 52 weeks on VAS and SNOT-22 scores was then determined using these thresholds using unblinded data. Results Internal consistency was acceptable for VAS and SNOT-22 scores (Cronbach’s α-coefficients ≥ 0.70). Test–retest reliability was demonstrated for all symptom VAS (Intra-Class Correlation coefficients > 0.75). Construct validity was acceptable between individual and composite VAS and SNOT-22 total score (r = 0.461–0.598) and between individual symptom VAS and corresponding SNOT-22 items (r = 0.560–0.780), based upon pre-specified ranges. Known-groups validity assessment demonstrated generally acceptable validity based on factors associated with respiratory health, with all VAS responsive to change. Mepolizumab treatment was associated with significantly increased odds of meeting or exceeding meaningful within-patient change thresholds, derived for this very severe cohort using six anchor groups for individual VAS (odds ratio [OR] 2.19–2.68) at Weeks 49–52, and SNOT-22 (OR 1.61–2.96) throughout the study. Conclusions Symptoms VAS and SNOT-22 had acceptable psychometric properties for use in very severe CRSwNP. Mepolizumab provided meaningful within-patient improvements in symptom severity and health-related quality of life versus placebo, indicating mepolizumab provides substantial clinical benefits in very severe CRSwNP. Supplementary Information The online version contains supplementary material available at 10.1186/s41687-023-00543-5.


Background
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of CRS, characterized by persistent inflammation of the paranasal sinuses [1][2][3]. Inflammation is typically eosinophilic in nature, driven by type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13 [4,5], resulting in symptoms of nasal blockage, loss of sense of smell, nasal discharge and/or facial pain [1,6]. The current standard of care (SoC) for CRSwNP includes intranasal corticosteroids, saline nasal irrigation, short courses of systemic corticosteroids (SCS) for exacerbations, and sinus surgery when appropriate medical therapy fails [1]. However, these treatments have substantial limitations, including adverse events associated with SCS use, and nasal polyp (NP) recurrence following surgery [7,8], highlighting the need for new, effective treatment options.
The anti-IL-5 humanized monoclonal antibody mepolizumab is approved for the treatment of CRSwNP in the US and EU [9][10][11]. In patients with CRSwNP in previous Phase II trials, mepolizumab has been shown to improve symptoms, reduce NP size and reduce the need for sinus surgery compared with placebo [12,13]. In addition, results from SYNAPSE, a Phase III trial have shown that in adults with very severe CRSwNP in need of revision surgery, 4-weekly mepolizumab 100 mg subcutaneously (SC) plus SoC significantly improved NP size and nasal obstruction versus placebo, with no new safety findings found in addition to those previously reported in patients with CRSwNP treated with mepolizumab [12][13][14].
Since CRSwNP significantly impacts health-related quality of life (HRQoL) [12,15,16], clinical trials assessing the efficacy of novel treatments in patients with CRSwNP have included patient-reported outcome measures (PROMs) to evaluate symptom severity (HRQoL via the use of, for example, the visual analogue scale (VAS) and Sino-nasal Outcome Test (SNOT)-22, respectively, as supported by the European Position Paper on Rhinosinusitis and Nasal Polyposis (EPOS 2020) [1]. The psychometric properties of the VAS were assessed in a Phase II study assessing mepolizumab clinical efficacy in CRSwNP [17]. The analyses indicated that although overall patient comprehension of the VAS was good, there was room for improvement. Consequently, to improve clarity (and therefore data quality) of the VAS, modifications were made to the item names and the verbal descriptors, the facial pain/pressure VAS item was added, and a 24-h recall period was implemented for use in the Phase III SYNAPSE study [14,18]. As VAS is a key endpoint in CRSwNP research, it was necessary to repeat the psychometric analysis of the modified VAS using Phase III data. Furthermore, as the score interpretation thresholds available to assess treatment response in CRSwNP trials are based on a CRSwNP population of mixed severity [19,20], information on thresholds required for patients with the most severe disease was needed as the burden of symptoms in patients with severe CRSwNP is high and has a significant impact on HRQoL [21]. Indeed, the need for different thresholds for patients with the most severe disease has been demonstrated in the asthma field [19,22]. As such, the objectives of this post hoc analysis were two-fold. First, to evaluate the psychometric properties of VAS scores and derive meaningful within-patient change thresholds for VAS and SNOT-22 in patients with very severe CRSwNP using blinded data from SYN-APSE. Second, patients were classified as responders or non-responders using meaningful within-patient change thresholds thereby assessing the efficacy of mepolizumab 100 mg SC administered every 4 weeks on symptom severity and HRQoL in adults with very severe CRSwNP.

Study design and patients
SYNAPSE was a Phase III randomized, double-blind, placebo-controlled, parallel-group trial (GSK205687; NCT03085797; Additional file 1: Figure S1) [14]. Patients (N = 407) were randomized (1:1) to mepolizumab 100 mg SC (n = 206) or placebo (n = 201) every 4 weeks, for 52 weeks in addition to SoC, including daily mometasone furoate nasal spray throughout the study period, saline nasal irrigations, and courses of SCS and/or antibiotics, as required [14]. Patient eligibility criteria included having a diagnosis of very severe CRS, characterized by (1) the presence of recurrent, refractory severe bilateral NP symptoms, (2) ≥ 1 prior surgery for NPs (a procedure involving instruments with resulting tissue removal) in the past 10 years, and 3) a current need for surgery (defined as an overall symptoms VAS score > 7 and endoscopic NP score of ≥ 5 [maximum 8], with a score ≥ 2 in each nasal cavity). Inclusion criteria for this study resulted in patients with very severe CRSwNP [14].

VAS and SNOT-22 assessments
Patients completed six individual VAS assessments daily (nasal obstruction, nasal discharge, mucus in the throat, loss of sense of smell, facial pain, and overall symptoms) using an electronic diary (eDiary) and a recall period of 24 h. For each VAS, patients rated their symptom on a scale from 'none' (0) to 'as bad as you can imagine' (100). Results were transformed linearly to a 0-10 range for reporting (higher scores indicated greater symptom severity); the psychometric properties were unaffected by this transformation.
Patients also completed SNOT-22 assessments every 4 weeks using the same electronic device and a recall period of 2 weeks. A total of 22 symptoms were rated on a 0-5 scale, with a final total score of 0-110 (higher scores indicated greater disease impact on HRQoL). Endpoints from SYNAPSE relevant to this analysis are listed in Additional file 1: Supplementary Methods.

Psychometric assessments
Blinded assessments of VAS and SNOT-22 were performed post hoc using data from the intent-to-treat population. Each VAS item was assessed separately, in addition to proposed four-item composite (nasal symptoms) and five-item composite (nasal symptoms and facial pain) scores (Additional file 1: Figure S2). Daily VAS scores at the Week 20 visit were used for confirmatory factor analysis (CFA) and internal consistency analyses; 4-week average VAS scores were used for analyses of the VAS over time, for example, testretest (assessed at Week 20 and Week 24). Key analysis time points for efficacy assessments were Baseline, Weeks 20, 24, and 52. Where available, Week 20 data were prioritized for cross-sectional psychometric analyses as this time point was expected to have maximal change from baseline in individual patient scores while maximizing the number of patients included in the analyses (minimal patient drop out at this time point). Floor and ceiling effects, test-retest reliability, knowngroup validity, and ability to detect change were not assessed for SNOT-22 as these have been previously demonstrated [14]. No imputation of missing data was performed; 4-week averages were derived based on all available data within that timeframe.

Item characteristics
VAS ceiling and floor effects were explored, defined as > 15% of patients selecting the most severe health state ('worst imaginable' [ceiling]) or least severe health state ('none' [floor]) [23]. However, owing to the severity of the CRSwNP in patients included in this study, it was anticipated that scores would be distributed towards the higher end of the scale at baseline and ceiling effects may have been present at this time point. Inter-item correlations were therefore assessed for the individual symptom VAS scores (Spearman's correlations to allow for violation of normality) and the SNOT-22 items (polychoric) at Week 20. Items that correlated very highly with one another (r ≥ 0.90) were flagged as potentially indicating redundancy.  [24,27,28].

Reliability
Internal consistency, the extent to which responses to individual items within a score are interrelated, was investigated for both VAS composite scores and the SNOT-22 by calculating Cronbach's α coefficient for each score, with a coefficient ≥ 0.70 considered acceptable [29]. Test-retest reliability, the degree to which scores are similar between two time points in patients who are stable, was evaluated for the individual symptoms VAS, overall symptoms VAS and both VAS composite scores by calculating the Intra-Class Correlation (ICC) coefficient for VAS and assessing stability between Weeks 20 and 24 (Additional file 1: Table S1). The ICC was based on a multiple measurement, absolute agreement, twoway random effects model (equivalent to ICC 2,k) [ [36], and Work Productivity and Activity Impairment (WPAI) Questionnaire (absenteeism, presenteeism, work productivity loss and activity impairment) (Additional file 1: Table S2) [37]. Correlations were based on predefined ranges (high: ≥ 0.50, medium: ≥ 0.30 to < 0.50, low: < 0.30) [38]. The known-groups method (to differentiate between clinically distinct groups [29]) was used to evaluate the construct validity of the individual and overall symptoms VAS and both composite VAS scores. VAS scores were compared in patients grouped according to ranges of key baseline characteristics: comorbid asthma, baseline blood eosinophil count categories, non-steroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), Asthma Control Questionnaire (ACQ)-5 score in patients with comorbid asthma and number of prior surgeries [39]. Between-group effect size estimates were calculated as per Hedges 1981 [39], and effect sizes (ES) were interpreted as small (ES = 0.20), moderate (ES = 0.50), and large (ES = 0.80) [38]. The statistical significance (P ≤ 0.05) of differences in scores between groups was calculated using the F-test of one-way analysis of variances.

Interpretation of scores: meaningful within-patient improvements
Thresholds for meaningful within-patient change were derived to determine the proportion of responders for subsequent unblinded analyses. Anchor-based analyses were performed for individual and overall VAS symptoms and both composite VAS scores and the SNOT-22 total score using data from baseline to Week 52. Potential anchors included in this exploratory analysis were endoscopic NP score, PNIF, overall VAS and SNOT-22, none of which have been established as verified anchors and no meaningful changes have been reported for overall VAS and endoscopic NP scores. Polyserial correlations were used to assess the relationship between potential anchors and change in VAS scores; anchors with a coefficient of ≥ 0.3 were selected [40]. Anchors that were deemed to have a sufficient relationship with the PROM scores were used to define patients as minimally improved or stable as described in Additional file 1: Table S3. Definition justifications are also provided in Additional file 1: Table S3 and were based on clinical insight, published literature and patient input. As recommended by the Food and Drug Administration, [41,42] descriptive statistics within each anchor category were supplemented with cumulative distribution function (CDF) and probability density function (PDF) plots. These were split by anchor categories to compare estimated thresholds for meaningful within-patient changes in VAS scores and SNOT-22 scores from baseline to Week 52 in this very severe CRSwNP population. The use of group-level statistics to estimate within-individual change thresholds has been contested owing to individual patients varying in their own personal threshold for meaningful improvement; however, when the objective of an analysis is to use these thresholds to estimate the proportion of responders in a population, this estimated responder rate should still be valid [43]. In addition, it has been recommended that the statistical significance of individual-level change should inform use of within-patient thresholds; [44] this was assessed by the 95% coefficient of repeatability (1.96*√2*standard error of measurement).

Response to treatment
Mepolizumab efficacy versus placebo on VAS and SNOT-22 was determined using the meaningful within-patient change thresholds for individual and overall symptoms VAS and for the SNOT-22 total score. Meaningful within-patient changes were analyzed using a logistic regression model with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count. Additional analysis details are included in Additional file 1: Supplementary Methods.

Patient population
Of the 407 patients included in SYNAPSE, 206 received mepolizumab and 201 received placebo. Overall, patients were mostly male (65%) with a mean (SD) age of 48.8 (13.0) years. The median baseline VAS and SNOT-22 total scores were similar between treatment groups (Table 1).

VAS psychometric analysis Item characteristics
The individual symptom VAS scores were clustered at the high end of the scale at baseline, owing to the severity of symptoms present in the population. VAS responses were distributed across the full response scale at Weeks 20, 24 and 52. Ceiling effects were present at all time points for the loss of smell VAS, and a floor effect was observed for the facial pain or pressure VAS at Week 52. While no other VAS demonstrated substantial floor or ceiling effects, a higher proportion of responses were clustered at the upper versus lower end of the scale for all VAS scores at baseline (as was expected owing to the eligibility criteria), but not during the treatment period (Additional file 1: Figure S3). All correlations between single VAS items were acceptable (> 0.3), with correlations > 0.9 observed only between two pairs of VAS: nasal obstruction VAS and nasal discharge VAS (r = 0.929), and nasal discharge VAS and mucus in throat VAS (r = 0.900). While a correlation of > 0.9 may show proof of redundancy, all items were included in the final model, as these item pairs include symptoms highly important to patients [21].

Domain structure
CFA using Week 20 data found that standardized loadings were ≥ 0.40 for the unidimensional nasal symptoms composite VAS score, and nasal symptoms and facial pain composite VAS score. Further details of model fit are included in Additional file 1: Supplementary Results. Residual correlations were not suggested (by modification indices > 10, to capture a critical value of 10.83 corresponding to P < 0.001 [45]) between the pairs of items with high inter-item correlations but were suggested between nasal obstruction and loss of smell.

Reliability
Cronbach's α coefficients indicated acceptable internal consistency and reliability. For both nasal symptoms composite VAS score, and nasal symptoms and facial pain composite VAS scores, coefficients exceeded the predefined acceptable threshold of ≥ 0.70 at Week 20 (0.910 and 0.926) and Week 52 (0.904 and 0.926). To evaluate test-retest reliability, ICC coefficients between scores at Weeks 20 and 24 were assessed in a subset of participants defined as stable (Additional file 1: Table S1). All ICCs for individual symptom VAS, Overall VAS and both composite scores exceeded the prespecified threshold of > 0.75, with the lower 95% confidence intervals (CIs) of all estimates > 0.90 (indicating 'excellent' reliability).  Table S2).
Known-groups validity assessment demonstrated generally acceptable validity based on comorbid asthma, blood eosinophil count and N-ERD. Statistically significant between-group differences (F-test P < 0.05), with small to large effect sizes (ES range 0.20 to 0.80), on several VAS were noted for ACQ-5 score and number of prior surgeries at Week 20 (Additional file 1: Table S4).

Responsiveness
In the ability to detect change analysis, effect sizes (− 3.61 to − 8.84) reported using all anchors indicated very large changes in the improved groups across all VAS and both composite scores. Changes in VAS scores were also large within the stable groups (ES − 0.48 to − 5.02), although always smaller than those in the improved groups.

Interpretation of scores
Anchors based on the SNOT-22 (polyserial correlation coefficient range: − 0.436 to − 0.599) and overall symptoms VAS (polyserial correlation coefficient range: − 0.768 to − 0.974) were sufficiently correlated (r ≥ 0.3) with change in VAS scores and thus suitable for use. Mean anchor-based changes from baseline to Week 52 in VAS scores for patients categorized as stable or minimally improved (Table 2), CDF plots (Additional file 1: Figures S4-S10) and PDF plots informed meaningful  within-patient change improvement thresholds of − 2.5 points for the overall symptoms, nasal discharge, and facial pain VAS, and − 3.0 points for the nasal obstruction, loss of sense of smell, and mucus in throat VAS. The absolute magnitude of these thresholds (threshold divided by SD) ranged from 0.76 to 1.14 in standardized units. The selection of these thresholds was largely driven by the CDF plots, where each was generally deemed sensitive enough to capture most minimally improved patients while specific enough to exclude the majority of stable patients across the different anchors. Estimates for the 95% coefficient of repeatability ranged from 1.00 to 2.13, suggesting that all thresholds represent statistically significant within-individual changes [44].

SNOT-22 psychometric analysis Item characteristics
Inter-item correlations between each possible pairing of the 22 individual items of the SNOT-22 were medium to high (r > 0.3) and there was no item redundancy (i.e. r ≥ 0.9).

Reliability and validity
Cronbach's α was ≥ 0.70 at Weeks 20 (0.963) and 52 (0.961), further supporting acceptable internal consistency reliability of the SNOT-22 total score. The CFA of SNOT-22 data supported the six-domain model with second order symptoms and impact factors (Fig. 1). All standardized loadings were ≥ 0.40, indicating that all SNOT-22 items were adequate indicators of their respective factors [26], and the validity of the SNOT-22 total score was also supported due to the high correlation between the second order symptoms and impact factors (r = 0.792). Global fit statistics were acceptable for RMSEA (0.089) and SRMR (0.064) but not CFI (0.897) and Chi-square (P < 0.001).

Interpretation of scores
Although overall symptoms VAS is not a verified anchor, it was identified as the overall measure of stability and  (Fig. 2). CDF (Fig. 3) and PDF plots suggested that a − 28-point change was sensitive enough to capture most improved patients while being specific enough to exclude the majority of stable patients, within this very severe population. The absolute magnitude of this threshold (threshold divided by SD) was 1.25 in standardized units. This 28-point threshold is close to 50% of the mean change from baseline in SNOT-22 total score observed in SYNAPSE. Therefore, 50% of the baseline score may be a plausible general threshold to use beyond this particular, very severe CRSwNP population. The 95% coefficient of repeatability was 11.89, suggesting a threshold of ≥ 28 points represents a statistically significant within-patient change [44].

VAS response to treatment
Compared with placebo, patients receiving mepolizumab had significantly increased odds (odds ratio [OR] 2.19-2.68) of achieving a meaningful improvement in individual VAS scores, based on meeting or exceeding the meaningful within-patient change thresholds at Weeks 49-52 (Fig. 4). Mepolizumab treatment was associated with a significantly greater change from baseline in individual VAS scores compared with placebo at Weeks 49-52 (P < 0.001) (Fig. 5). Patients who had undergone ≥ 2 surgeries versus 1 surgery prior to mepolizumab treatment showed less improvement in median change from baseline in loss of sense of smell VAS (Fig. 6).

SNOT-22 response to treatment
A total of 54% and 32% of patients treated with mepolizumab and placebo achieved a ≥ 28-point improvement in SNOT-22 total scores, respectively (Additional file 1: Table S5). Patients receiving mepolizumab had significantly increased odds (OR 1.61-2.96) of achieving a ≥ 28-point improvement in SNOT-22 total score at each 4-weekly time points from Week 4-52 (Fig. 7). There were also significant improvements (P < 0.001) in the mean change from baseline in SNOT-22 total and  item scores following mepolizumab treatment compared with placebo at Week 52 (Fig. 8).

Discussion
Using data from SYNAPSE, this analysis evaluated the psychometric properties of the VAS and SNOT-22 in a blinded manner and determined the proportion of responders to mepolizumab using meaningful within-patient change thresholds for these measures, relevant to this population with very severe CRSwNP. Findings indicate that the VAS and SNOT-22 perform well and have acceptable psychometric properties in this very severe CRSwNP population. They also indicate that mepolizumab provided meaningful withinpatient improvements in HRQoL versus placebo when added to standard of care. This indicates mepolizumab provides substantial clinical benefits in very severe CRSwNP. Mepolizumab 100 mg SC (n=205) to placebo (n=198); OR (95% CI)  VAS item responses were selected across the range at Weeks 20, 24, and 52. While a higher proportion of responses were clustered at the upper versus lower end of the scale for all symptom VAS scores at baseline, this was expected owing to the very severe CRSwNP SYNAPSE eligibility criteria. No substantial floor or ceiling effects were seen during the treatment period except for a floor effect for loss of sense of smell across all time points. This was likely a result of the CRSwNP and the history of repeat nasal surgery in SYNAPSE patients, which can lead to permanent sense of smell impairment [46,47]. A floor effect was noted in the facial pain or pressure VAS at Week 52, likely because not all patients experience this symptom [21], and successful mepolizumab treatment will have potentially further decreased this proportion by the end of the study.
All correlations between single VAS items were acceptable, supporting the use of two VAS composite scores (symptoms composite, and nasal symptoms and facial pain composite). Factor structure of the VAS composite scores, as determined by CFA, was acceptable with the CFI and SRMR statistics. Although Chi-square and RMSEA model fit were initially not acceptable, model fit improved following the incorporation of conceptually justifiable residual correlations. Although the residual correlation suggested some redundancy in the VAS items, which can lead to overweighting in composite scoring, these items were still included in the VAS composite scores based on their believed importance to patients. Regarding the Chi-square test, the improvement in model fit may have been due to the model's tendency to reject the null hypothesis in large samples, such as the 407 patients included in this analysis, even when the hypothesized model shows trivial misfit.
The VAS scores demonstrated acceptable internal consistency and excellent test-retest reliability. The VAS also demonstrated construct validity between corresponding VAS and SNOT-22 items, consistent with a priori hypothesized correlations. Correlations between the VAS and UPSIT, endoscopic NP and PNIF were weaker than a priori hypothesized correlations, which may be indicative of differences between objective or clinician-reported measures and daily patient reports of CRSwNP disease severity. In contrast, correlations between VAS scores and WPAI impairment-based scores and SF-36 PCS exceeded predictions.
The VAS demonstrated acceptable validity based on several known-groups assessments and detected large effect sizes for all VAS scores using all anchors in patients determined to have improved. Psychometric analyses indicated a meaningful within-patient change threshold of − 2.5 points for overall symptoms, nasal discharge, and facial pain VAS and a threshold of − 3.0 points for nasal obstruction, loss of sense of smell, and mucus in throat VAS. This is consistent with previous studies indicating that a change of 2-3 points on a 0-10 VAS is considered a meaningful within-patient change [48,49], suggesting similar thresholds are appropriate across the spectrum of disease severity as reported elsewhere [50]. Interestingly, while it has been previously assumed that anchor-based mean estimates will be lower than the 95% coefficient of repeatability (underestimating the amount of change needed to be statistically significant at the individual level) [44], our empirical mean estimates were higher. This is likely due to the high reliability estimates observed, resulting in a small degree of measurement error. We also note that the recommended thresholds (guided by CDF and PDF plots in addition to the mean changes) were primarily between the 95% coefficient of repeatability and the anchor-based mean changes. Psychometric analyses of SYNAPSE confirm the validity of the SNOT-22 total score, as previously reported [14] and support a six-domain structure for reporting SNOT-22 results. Other studies have suggested four [51] or five [52] domains underlying the total score; however, the six-domain structure in this study was indicated by a previous analysis of patients with very severe CRSwNP in a clinical trial setting and thus may be most appropriate for analyzing SYNAPSE data [53]. These psychometric analyses also suggested that a ≥ 28-point improvement (~ 50% change from baseline) in SNOT-22 was an appropriate threshold to determine meaningful within-patient change within this very severe CRSwNP trial population. Different within-patient meaningful change thresholds may be more appropriate in less severe populations or clinical practice; this subject warrants future research. However, a 2010 study by Browne et al., which generated anchor-based values for within-patient meaningful changes for a number of commonly used PROMs suggested little association between baseline severity and within-patient meaningful change values as mathematical coupling can lead to an artificially inflated association between initial value and change score when correlation or regression is used [50]. Such a limitation should be considered when interpreting the results of the present study. In addition, Browne et al., advocated that an MCID should be calculated using a wide range of baseline severities and a single value applied across cohorts; [50] in the case of the SNOT-22 a value of 8.9 points might be appropriate regardless of baseline symptom burden.
The analyses of patient responses to treatment using the VAS and SNOT-22 demonstrated that patients with CRSwNP experienced significant clinical benefits in symptom severity and HRQoL with mepolizumab versus placebo. Furthermore, the effect of mepolizumab on loss of sense of smell measured by the VAS was greatest in patients who had undergone one versus multiple prior surgeries. This may be related to the increased scarring and nerve damage associated with repeat surgeries, limiting the recovery of sense of smell [46,47]. These results are consistent with results from SYNAPSE, which showed significant improvements in total endoscopic NP score, nasal obstruction VAS and SNOT-22 total score with mepolizumab versus placebo [14].
There were several limitations in the current analyses. Firstly, the psychometric analysis would have ideally used tailored 'global impression' anchor measures, specifically designed to evaluate meaningful change thresholds for the VAS and SNOT-22, rather than using the anchoring and triangulation of other outcome measures that were available at the time of this analysis. Use of an arbitrary overall symptoms VAS anchor may have overestimated changes in SNOT-22 score. Given this limitation, care was taken to justify the levels of change on each anchor considered a minimal improvement, where justification was based on clinical insight, published literature and patient input. However, we appreciate that our assumptions on what constitutes a minimal improvement are not guaranteed to precisely capture this level of change, and our chosen definitions may not be universally agreed upon. The suggested exploratory thresholds should therefore be confirmed in future research. Secondly, the same data were used to derive the meaningful within-patient thresholds and to determine the treatment response, which could be considered 'overfitting' the data. However, the psychometric analyses used data specific to the SYNAPSE trial in patients with very severe CRSwNP, therefore, the absolute values for respiratory threshold are likely not applicable in a less severe population. Furthermore, blinding the data to establish the thresholds mitigates the potential for overfitting. Thirdly, although the developer-recommended scoring of the SF-36v2 PCS and MCS has been contested, we did not explore alternate scoring options in detail [36,54]. Finally, the analysis is limited by the SYNAPSE study population of patients with at least one previous nasal surgery [14]. As such, it is important to note that these analyses and their outcomes apply only to the very severe CRSwNP population included in SYNAPSE.

Conclusions
These psychometric analyses demonstrate that both the VAS and SNOT-22 have acceptable psychometric properties for outcome assessment in patients with very severe CRSwNP. Scores derived from both measures exhibited acceptable internal consistency and construct validity, in addition to test-retest reliability and knowngroups validity (assessed only for the VAS). Overall, our analysis demonstrated that patients receiving mepolizumab were more likely to experience improvements